4-demethoxy-4-amino-anthracyclines

ABSTRACT

Anthracycline glycosides of the general formula (I): ##STR1## wherein R 1  represents a hydrogen atom or a hydroxyl group, one of R 2  and R 3  represents a hydrogen atom and the other of R 2  and R 3  represents a hydrogen atom or a hydroxyl group; and pharmaceutically acceptable acid addition salts thereof are antitumor agents. These glycosides may be prepared from a daunomycinone derivative of formula (II): ##STR2## in which the 4-amino group is protected. 4-Demethoxy-4-amino-daunomycinone (II) and an earlier intermediate in its preparation, 4-demethoxy-4-amino-7-deoxy-daunomycinone (IX), can be diazotized followed by mild reduction to form 4-demethoxy-daunomycinone or 4-demethoxy-7-deoxy-daunomycinone respectively. 4-Demethoxy-daunomycinone can be converted into another antitumor anthracycline glycoside, 4-demethoxy-daunorubicin.

This is a division of application Ser. No. 07/181,506, filed on April14, 1988, now abandoned.

The invention relates to anthracycline glycosides; to their preparation,to pharmaceutical compositions containing them and to intermediates foruse in the preparation of the anthracycline glycosides.

The invention provides anthracycline glycosides having the generalformula (I): ##STR3## wherein R₁ represents a hydrogen atom or ahydroxyl group, one of R₂ and R₃ represents a hydrogen atom and theother of R₂ and R₃ represents a hydrogen atom or a hydroxyl group, andtheir pharmaceutically acceptable addition salts. Preferred salts arethe hydrochloride salts. The compounds of formula (I) may be named asfollows:

Ia: R₁ =R₃ =H; R₂ =OH

4-demethoxy-4-amino-daunorubicin

Ib: R₁ =R₂ =OH; R₃ =H

4-demethoxy-4-amino-doxorubicin

Ic: R₁ =R₂ =H; R₃ =OH

4-demethoxy-4-amino-4'-epi-daunorubicin

Id: R₁ =R₃ =OH; R₂ =H

4-demethoxy-4-amino-4'-epi-doxorubicin

Ie: R₁ =R₂ =R₃ =H

4-demethoxy-4-amino-4'-deoxy-daunorubicin

If: R₁ =OH; R₂ =R₃ =H

4-demethoxy-4-amino-4'-deoxy-doxorubicin

The glycosides of formula (I) and their pharmaceutically acceptableaddition salts are prepared by a process which comprises

(i) reacting a protected derivative of a daunomycinone derivative offormula (II): ##STR4## wherein the 4-amino group is protected, with aprotected halosugar of formula (III) wherein one of R'₂ and R'₃represents a hydrogen atom, the other of R'₂ and R'₃ represents ahydrogen atom or a protected hydroxy group, the 3-amino group isprotected and Hal represent a halogen atom, and removing the protectinggroups from the product thus-obtained such as to obtain an anthracyclineglycoside of formula (I) wherein R₁ is hydrogen;

(ii) if desired, converting the said glycoside of formula (I) into apharmaceutically acceptable salt thereof;

(iii) if desired, brominating the said glycoside of formula (I) orpharmaceutically acceptable salt thereof and hydrolysing the 14-bromoderivative thus-obtained so as to form the corresponding glycoside offormula (I) wherein R₁ is hydroxy; and

(iv) if desired, converting the said glycoside of formula (I) wherein R₁is hydroxy into a pharmaceutically acceptable salt thereof.

Preferably, in step (i) the protected derivative of the daunomycinonederivative of formula (II) is4-demethoxy-4-N-trifluoroacetamido-daunomycinone. The protectedhalosugar is preferably a protected halosugar having the formula (IV):##STR5## wherein one of R"₂ and R"₃ represents a hydrogen atom, theother of R"₂ and R"₃ represents a hydrogen atom or a trifluoroacetoxygroup, and Hal is as defined above. Preferably Hal is a chlorine atom.

The condensation of 4-demethoxy-4-N-trifluoroacetamido-daunomycinone andthe protected halosugar (IV) may proceed in the presence of silvertriflate. The method described in U.S. Pat. No. 4,107,423 may be used,giving (7S,9S)-O-trifluoroacetyl protected derivatives of thea-glycosides. The 4-demethoxy-4-N-trifluoroacetamido-daunomycinone canbe dissolved in anhydrous methylene chloride with reaction proceeding at5° to 10° C. The N-protecting trifluoroacetyl groups may be removed bymild alkaline treatment.

Preferably, an anthracycline glycoside of formula (I) wherein R₁ ishydrogen is isolated in step (ii) as its hydrochloride. Subsequenttreatment of the resultant 4-demethoxy-4-amino-daunorubicin derivatives,in accordance with the method described in U.S. Pat. No. 4,067,969,affords the corresponding 4-demethoxy-4-amino-doxorubicins in step(iii). Hydrolysis may be effected with sodium formate. In step (iv), aresultant anthracycline glycoside of formula (I) wherein R₁ is hydroxypreferably is isolated as its hydrochloride.

The daunomycinone derivative of formula (II) and protected derivativesthereof wherein the 4-amino group is protected also form part of theinvention. These compounds may be prepared by a process which comprises:

(a) removing by hydrogenolysis the 7α-hydroxyl group of carminomycinoneof formula (V): ##STR6##

(b) reacting the resultant 4-demethyl-7-deoxy-daunomycinone of formula(VI): ##STR7## with 4-fluorobenzensulfonyl chloride in the presence ofN,N-diisopropylethylamine and a catalytic amount of4-dimethylaminopyridine;

(c) reacting the resultant4-demethoxy-4-O-[4-fluorobenzensulfonyl]-7-deoxy-daunomycinone offormula (VII): ##STR8## with benzylamine;

(d) removing the benzyl group from the resultant4-demethoxy-4-benzylamino-7-deoxy-daunomycinone of formula (VIII):##STR9## by catalytic hydrogenation;

(e) protecting the 4-amino group of the resultant4-demethoxy-4-amino-7-deoxy-daunomycinone of formula (IX): ##STR10##

(f) reintroducing the 7α-hydroxy group into the resultant compound offormula (X): ##STR11## wherein X' represents the amino protecting group,thereby obtaining a protected derivative of formula (XI) of adaunomycinone derivative of formula (II): ##STR12## wherein X' isdefined above; and

(g) if desired, removing the 4-amino protecting group from the protectedderivative of formula (XI), thereby obtaining the daunomycinonederivative of formula (II): ##STR13##

This process is illustrated in Scheme I below. The starting compound forthe process is the natural carminomycinone (V). The sulfonylationreaction, step (b), leads only the substituted C-4-O-sulfonyl derivative(VII), leaving the C-6-OH and C-11-OH unaffected. It should be stressedthat this unexpected selectivity has been achieved only under theconditions described herein. ##STR14##

Reaction (c) is a new one in anthracycline chemistry, probably due tothe withdrawing effect both of the quinone moiety and of the4-fluoro-benzensulfonyl group at the position C-4. Preferably, thereaction is effected in tetrahydrofuran at room temperature. Step (e) ispreferably effected with trifluoroacetic anhydride. Preferably,therefore X' represents a trifluoroacetyl group in formulae (X) and(XI). Step (f) may be performed according to the method described by C.M. Wong et al., Can. J. Chem., 51, 446 (1973). Preferably, it iseffected by protecting the 13-keto group of a 4-demethoxy-4-(protectedamino)-7-deoxy-daunomycinone compound of formula (XII): ##STR15## bytreatment with ethylene glycol; brominating the resultant compound atthe 7-position; and hydrolysing the 7-bromo and 13-ketal groups to give4-demethoxy-4-N-trifluoroacetamido-daunomycinone of formula (XIII):##STR16## Bromination is generally achieved by treatment with bromine orN-bromosuccinimide in the presence of 2,2'-azo-bis(isobutyronitrile).

The intermediates of formula (II) and (IX) are also useful for thepreparation of 4-demethoxy-7-deoxy-daunomycinone or4-demethoxy-daunomycinone. The intermediate4-demethoxy-4-amino-7-deoxy-daunomycinone of formula (IX) forms anadditional aspect of the invention, as does its preparation according tosteps (a) to (d) above. 4-Demethoxy-7-deoxy-daunomycinone can beconverted into 4-demethoxy-daunomycinone. Further antitumoranthracycline glycosides can be prepared from 4-demethoxy-daunomycinone.

According to the present invention, there therefore further is provideda process for preparing 4-demethoxy-7-deoxy-daunomycinone or4-demethoxy-daunomycinone of formula (XIV): ##STR17## in which R₄represents hydrogen or hydroxy, which process comprises diazotising the4-amino group of 4-demethoxy-4-amino-7-deoxy-daunomycinone or4-demethoxy-4-amino-daunomycinone of formula (XV): ##STR18## in which R₄is as defined above, and reducing under mild conditions the diazoniumcompound thus-formed.

Anthracyclinones bearing an amino group at position C-4 are thereforetransformed into their corresponding desamino derivatives. The startingcompounds are 4-demethoxy-4-amino-7-deoxy-daunomycinone (IX(XVa, R=H))and 4-demethoxy-4-amino-daunomycinone (II (XVb, R=OH)). The removal ofthe 4-amino group, via diazotisation and mild reduction, leads to thewell known 4-demethoxy-7-deoxy-daunomycinone (XIVa, R=H) or4-demethoxy-daunomycinone (XIVb, R=OH). As shown in Scheme II,diazotisation is preferably effected using aqueous sodium nitrite. Themild reduction is preferably effected using hypophosphorous acid.##STR19##

Compound XVa in which R₄ =H can be easily transformed into compound XVbin which R₄ =OH by standard methods. Preferably, the4-demethoxy-4-amino-7-deoxy-daunomycinone (XVa) or4-demethoxy-4-amino-daunomycinone (XVb), dissolved in aqueous 37%hydrochloric acid, is reacted at a temperature of from 0° to 5° C.⁻ andfor 1 hour with an aqueous solution of sodium nitrite and, subsequently,for 5 hours at room temperature under vigorous stirring with an aqueoussolution of 50% hypophosphorous acid, the reaction mixture is extractedwith methylene dichloride and the solvent is removed under reducedpressure.

4-Demethoxy-7-deoxy-daunomycinone (XIVa) may be converted into4-demethoxy-daunomycinone (XIVb) by introducing a hydroxy group at the7-position. This can be achieved according to the invention bybromination of the 7-position, for example by bromine orN-bromo-succinimide (NBS), followed by treatment with alkali or withsilver acetate or methanolysis of the acetate thus formed.

4-Demethoxy-daunomycinone (XIVb) is the aglycone moiety of the usefulantitumor drug 4-demethoxy-daunorubicin (XVI). Accordingly, the presentinvention further provides a process for preparing4-demethoxy-daunorubicin of formula (XVI): ##STR20## or apharmaceutically acceptable salt thereof; which process comprisesreacting 4-demethoxy-daunomycinone, which is represented by formula(XIV) in which R₄ is hydroxy and which has been prepared from4-demethoxy-4-amino-daunomycinone by a process according to theinvention, with an appropriate sugar derivative and, if desired,converting the 4-demethoxy-daunorubicin thus-obtained into apharmaceutically acceptable salt thereof.

The sugar derivative may have the formula (XVII): ##STR21## wherein Halrepresents a halogen atom, R₆ represents a protected hydroxy group andR₇ represents a protected amino group. The protecting groups are removedafter reaction with 4-demethoxy-daunomycinone. Preferably Hal is achlorine atom. The hydroxy group may be protected by a trifluoroacetylgroup. The amino group may be protected by a trifluoroacetyl group also.

The invention also provides pharmaceutical compositions comprising apharmaceutically acceptable carrier or diluent and

an anthracycline glycoside of formula (I) or a pharmaceuticallyacceptable salt thereof, or

an anthracycline glycoside of formula (XVI) or a pharmaceuticallyacceptable salt thereof which has been prepared as above.

Conventional formulations, carriers and diluents may be used. Thecompositions for administration to a patient comprise a therapeuticallyeffective amount of a glycoside. Thus, a therapeutically effectiveamount of a glycoside can be administered, by a conventional route, to ahuman patient.

The glycosides are antitumor agents. The activity of a representativecompound of formula (I), 4-demethoxy-4-amino-daunorubicin (Ia), has beenassessed by comparing its in vitro cytotoxicity against that ofdaunorubicin (DNR) in human colon adenocarcinoma cells sensitive (LoVo)or resistant (LoVo/DX) to doxorubicin. The results are shown in Table 1:

                  TABLE 1                                                         ______________________________________                                        Colony inhibition test after 4 h. treatment.                                                LoVo       LoVo/DX                                              Compound      ID.sub.50 (ug/ml)                                                                        ID.sub.50 (ug/ml)                                    ______________________________________                                        Ia            0.7        99                                                   DNR           50.3       1805                                                 ______________________________________                                    

The in vivo activities of (Ia) and DNR against disseminated Grossleukaemia in mice also determined. The results are shown in Table 2:

                  TABLE 2                                                         ______________________________________                                        Treatment i.v on day 1 after tumor inoculum                                   Compound  mg/Kg         T/C %   TOX                                           ______________________________________                                        DNR       10            133     0/10                                                    15            167     0/10                                                    22.5          200     1/10                                          Ia        1.6           183     0/10                                                    1.9           192     0/10                                                    2.29          200     1/10                                          ______________________________________                                         TC % represents,                                                              TOX represents toxic death                                               

The following Examples illustrate the invention.

EXAMPLE 1 4-Demethyl-7-deoxy-daunomycinone (VI)

1.5 g of 4-demethyl-daunomycinone (V) dissolved in a mixture of 100 mlof dioxane and 100 ml of ethanol was hydrogenated in the presence of 0.3g of 5% Pd-BaSo₄ at room temperature for 3 hours. After filtration thesolvent was removed in vacuo and 4-demethyl-7-deoxy-daunomycinone (VI)was recovered in almost quantitative yield. TLC on kieselgel F254(Merck) using Toluene:Acetone (9:1 by volume) Rf=0.30.

EXAMPLE 2 4-Demethyl-4-O-(4-fluoro-benzensulfonyl)-7-deoxy-daunomycinone(VII)

To a stirred solution of 1.0 g of 4-Demethyl-7-deoxy-daunomycinone (VI)in 200 ml of anhydrous methylene dichloride containing 0.52 ml ofN,N-diisopropylethylamine and a catalytic amount of4-dimethylaminopyridine, at room temperature, was added 0.52 g of4-fluoro-benzensulfonylchloride. After 30 minutes the transformation wascomplete and the reaction mixture was washed with 0.1N aqueoushydrochloric acid, then water.

The organic solution was dried over anhydrous sodium sulphate, thesolvent filtered off was and removed in vacuo. The crude product waspicked up with a little toluene and crystallized to give 0.6 g of pure4-demethyl-4-O-sulfonate derivative of formula IV. Others 0.3 g ofproduct was recovered by purification of the liquor through achromatographic column using as eluant a mixture of toluene/acetone.Yield 80%.

TLC on Kieselgel F254 (Merck) using Toluene:Acetone (9:1 by volume)Rf=0.26.

FDMS [M·⁺ ] 526.

UVλ_(max) (MeOH): 524, 490 nm.

1HNMR (200 MHz, CDCl₃ δ: 13.43, 13.36 (s, 2H, 11-OH, 6-OH), 8.38 (dd,J=1.3, 7.9 Hz, 1H, 1-H) 8.02 (m, 2H, ##STR22## 7.80 (dd, J=7.9, 8.1 Hz,1H 2-H), 7.62 (dd, J=1.3, 8.1 Hz, 1H, 3-H), 7.23 (m, 2H, 3.77 (s, 1H,9-OH), 3.1-2.8 (m, 4H, 7-CH₂, 10-CH₂), 2.38 (s, 3H, COCH₃), 2.0-1.9 (m,2H, 8-CH₂).

EXAMPLE 3 4-Demethoxy-4-benzylamino-7-deoxy-daunomycinone (VIII)

0.8 g of compound VII was dissolved with 100 ml of tetrahydro furane and0.5 ml of benzylamine was added.

The mixture was kept at 40° C. for 36 hrs under stirring, then 50 ml of1N aqueous hydrochoric acid and 100 ml of methylene dichloride wereadded.

The organic phase was washed twice with water and dried over anhydroussodium sulphate.

The solvent was removed in vacuo. The crude product was chromatographedby flash-chromatography, using as eluting solvent a mixture of tolueneand acetone, to give 0.48 g of the4-demethoxy-4-benzylamino-7-deoxy-daunomycinone (VIII). Yield 69%.

TLC on Kieselgel plate F254 (Merck) using Toluene:Acetone (9:1 byvolume) Rf=0.28.

FDMS [M·⁺ ] 457.

UVλ_(max) (MeOH): 548 nm.

1HNMR (200 MHz, CDCl₃) δ: 13.58 (s, 2H, 6-OH, 11-OH), 9.86 (t, J=5.7 Hz,1H, NH-CH₂ Ph), 7.64 (d, J=7.3 Hz, 1H, 1-H), 7.49 (dd, J=7.3, 8.3 Hz,1H, 2-H), 7.4-7.2 (m, 5H, NHCH₂ Ph), 7.00 (d, J=8.3 Hz, 1H, 3-H), 4.60(d, J=5.7 Hz, 2H, NHCH₂ Ph), 3.1-2.9 (m, 4H, 10-CH₂, 7-CH₂), 2.37 (s,3H, COCH₃), 2.0-1.9 (m, 2H, 8-CH₂).

EXAMPLE 4 4-Demethoxy-4-amino-7-deoxy-daunomycinone (IX)

0.45 g of 4-demethoxy-4-benzylamino-7-deoxy-daunomycinone (VIII), wasdissolved with a mixture of 40 ml of ethanol, 20 ml of acetic acid and0.4 ml of 37% aqueous hydrochloric acid.

0.2 g of 5% Pd/BaSO₄ catalyst was added and the mixture was hydrogenatedat 1 Atm. for 1 hr at room temperature. After that the catalyst wasremoved by filtration and the solvent evaporated in vacuo.

The crude product was chromatographed by flash chromatography using aseluent a mixture of toluene and acetone to give 0.2 g (yield 75%) of4-demethoxy-4-amino-7-deoxy-daunomycinone (IX).

TLC on Kieselgel plate F254 (Merck) using Toluene:Acetone (9:1 byvolume) Rf=0.17.

FDMS [M·⁺ ] 367.

UVλ_(max) (MeOH): 536, 508 nm.

1HNMR (200 MHz, CDCl₃)δ: 13.62, 13.55 (s, 2H, 11-OH, 6-OH), 7.64 (d,J=7.7 Hz, 1-H), 7.46 (dd, J=7.7, 8.3 Hz, 1H, 2-H), 6.93 (d, J=8.3 Hz,1H, 3-H), 6.8-7.0 (broad signal, 2H, NH₂), 3.83 (s, 1H, 9-OH), 3.1-2.8(m, 4H, 7-CH₂, 10-CH₂), 2.37 (s, 3H, COCH₃), 2.0-1.9 (m, 2H, 8-CH₂).

EXAMPLE 5 4-Demethoxy-4-N-trifluoroacetamido-7-deoxy-daunomycinone (XII)

0.2 g of 4-demethoxy-4-amino-7-deoxy-daunomycinone (IX), was dissolvedin 20 ml of anhydrous methylene dichloride, cooled at 0° C. and 0.3 mlof trifluoroacetic anhydride added. After 10 minutes aqueous sodiumhydrogen carbonate was added.

The organic phase was washed twice with water and separated off, driedover anhydrous sodium sulphate. The solvent was removed in vacuo to givea quantitative yield of compound XII.

TLC on Kieselgel F254 (MercK) using Toluene Acetone (9:1 by volume)Rf=0.32.

EXAMPLE 6 4-Demethoxy-4-N-trifluoroacetamido-daunomycinone (XIII)

A suspension of 0.2 g of compound XII in 15 ml of benzene and 0.5 ml ofethylene glycol was refluxed for 4 hr in presence of 0.015 g ofp-toluensulfonic acid using a Dean-Stark apparatus.

The mixture was cooled, washed with aqueous sodium hydrogen carbonateand water, then was evaporated to dryness to give 0.2 g of the expectedketal.

The latter was dissolved in 125 ml of methylene dichloride at 40° C. andwas treated with bromine (1.7 ml of 0.6M solution in methylenedichloride) in presence of 0.25 g of 2,2'-azobisisobutironitrile.

After 3 hr the mixture was cooled and extracted with aqueous sodiumhydrogen carbonate, then was washed twice with methylene dichloride andthe solvent removed in vacuo. This residue was dissolved in 3 ml oftrifluoroacetic acid and 0.3 ml of water at 0° C. and stirred for 1 hr,then extracted with methylene dichloride.

The organic phase was washed with aqueous sodium hydrogen carbonate andwater. The solvent was filtered off, dried over anhydrous sodium sulfateand evaporated in vacuo to give 0.1 g of4-demethoxy-4-N-trifluoroacetamido-daunomycinone (XIII), yield 48%.

TLC on Kieselgel plate F 254 (Merck) using CH₂ Cl₂ Acetone (95:5 byvolume) Rf=0.23.

FDMS [M·⁺ ] 479.

EXAMPLE 7 4-Demethoxy-4-amino-daunomycinone (II)

0.1 g of the 4-amino protected derivative XIII was poured in a mixtureof 20 ml of methanol and 10 ml of aqueous sodium hydrogen carbonate andstirred for 1 hour, then was added with aqueous hydrochloric acid andmethylene dichloride. The organic layer was separated and washed withwater, the solvent was removed in vacuo to give 0.8 g of4-demethoxy4-amino-daunomycinone (II).

TLC on Kieselgel plate F 254 (Merck) using CH₂ Cl₂ (95:5 by volume)Rf=0.10.

FDMS [M·⁺ ] 383.

1HNMR (200 MHz, CDCl₃)δ: 14.00 (s, 1H, 6-OH), 13.52 (s, 1H, 11-OH), 7.64(d,J=8.0 Hz, 1H, 1-H), 7.46 (t, J=8.0 Hz, 1H, 2-H), 6.93 (d, J=8.0 Hz,1H, 3-H), 6.80 (broad, 2H, 4-NH₂), 5.32 (ddd, J=2.0, 4.8, 4.8 Hz, 1H,7-H), 4.54 (s, 1H, 9-OH), 3.74 (d, J=4.8 Hz, 1H, 7-OH), 3.17 (dd, J=2.0,19.0 Hz, 1H, 10e-H), 2.92 (d, J=19.0 Hz, 1H, 10ax-H), 2.45 (s, 3H,COCH₃), 2.35 (ddd, J=2.0, 2.0, 15.0 Hz, 1H, 8e-H, 2.14 (dd, J=4.8, 15.0Hz, 1 H, 8ax-H). EXAMPLE 8

4-demethoxy-4-amino-daunorubicin (Ia)

0.08 g of 4-demethoxy-4-N-trifluoroacetamido-daunomycinone (XIII),prepared as described in Example 6, was dissolved in anhydrous methylenedichloride and the solution was cooled to 5°-10° C. A solution of 0.024g of 1-chloro-N,O-ditrifluoroacetyl-daunosamine, prepared following theprocedure described in Cancer Chemotherapy Reports, Part 3, Vol. 6, No.2, p. 123, in diethyl ether and a solution of 0.150 g of silvertrifluoromethanesulphonate in methylene dichloride were addedsimultaneously and rapidaly under vigorous stirring.

After 5 minutes, a further 0.070 g of silver trifluoromethane sulphonatewere added and after 5 minutes the reaction was quenched with collidine.

The mixture was filtered, washed with a satured aqueous solution ofsodium hydrogen carbonate and with water, dried and concentrate undervacuum.

The residue was chromatographed on a column of silica gel eluting withmethylene dichloride, to give4-demethoxy-4-N-trifluoroacetamido-N-trifluoroacetyl-daunorubicin (Ia).

The compound was dissolved in 10 ml of acetone and treated with 30 ml of0.1N aqueous sodium hydroxide at 0° C. for 3 hours. Then to the solutionwas added 0.1N aqueous hydrochloric acid to adjust the pH to 4.5 and theaglycone were eliminated by extraction with methylene dichloride. Thenthe aqueous solution was adjusted to pH 8.6 and extracted with methylenedichloride, dried over anhydrous sodium sulphate, concentrated to asmall volume and acidified to pH 4.5 with 0.1N methanolic hydrogenchloride to give the title compound as its hydrochloride.

EXAMPLE 9 4-demethoxy-4-amino-doxorubicin (Ib)

Following the process described in U.S. Pat. No. 3,803,124 and using asstarting material 4-demethoxy-4-amino-daunorubicin, prepared asdescribed in Example 8, the title compound was isolated as thehydrochloride.

EXAMPLE 10 Preparation of 4-demethoxy-7-deoxy-daunomycinone (XIVa)

1.78 g (5 mmol) of 4-demethoxy-4-amino-7-deoxy-daunomycinone (IX)dissolved with 75 ml of aqueous 37% hydrochloric acid, was cooled at0°-5° C. and 75 ml of an aqueous solution containing 0.6 g of sodiumnitrite is added. The mixture is stirred for one hour at 0°-5° C. Then75 ml of an aqueous solution of 50% hypophosphorous acid is added andthe mixture is kept at room temperature for five hours under vigorousstirring.

The solution is diluted with 200 ml of water and extracted withmethylene dichloride. The organic layer is separated off, dried overanhydrous sodium sulphate and the solvent is removed under reducedpressure to give a quantitative yield (1.7 g) of4-demethoxy-7-deoxy-daunomycinone (XIVa), analytically compared with astandard sample.

EXAMPLE 11 Preparation of 4-demethoxy-daunomycinone (XIVb)

1.86 g (5 mmol) of 4-demethoxy-4-amino-daunomycinone (II) aretransformed into the corresponding 4-demethoxy-daunomycinone (XIVb)following the method above described. Yield: 1.8 g of compound XIVbanalytically compared with a standard sample.

We claim:
 1. A daunomycinone of formula (II) ##STR23## or a 4-protectedamino derivative thereof.
 2. The daunomycinone of claim 1, wherein saidcompound is 4-demethoxy-4-N-trifluoroacetamidodaunomycinone.
 3. Aprocess for the preparation of a daunomycinone of formula (IX) ##STR24##comprising the steps of: (a) removing by hydrogenolysis, the 7α-hydroxylgroup of a carminomycinone of formula (V) ##STR25## (b) reacting theresulting 4-demethyl-7-deoxy-daunomycinone of formula (VI) ##STR26##with a 4-fluorobenzenesulfonyl chloride in the presence ofN,N-diisopropylethylamine and a catalytic amount of4-dimethylaminopyridine,(c) reacting the resulting4-demethoxy-4-O-[4-fluorobenzenesulfonyl]-7-deoxy-daunomycinone offormula (VII) ##STR27## with benzylamine, (d) removing the benzyl groupfrom the resulting 4-demethoxy-4-benzylamino-7-deoxy-daunomycinone offormula (VIII) ##STR28## by catalytic hydrogenation.
 4. The process ofclaim 3, further comprising:(e) protecting the 4-amino group of the4-demethoxy-4-amino-7-deoxy-daunomycinone of formula (IX) resulting fromstep (d) ##STR29## (f) reintroducing the 7α-hydroxy group into theresulting compound of formula (X) ##STR30## wherein X' is anamino-protecting group, thereby obtaining a protected derivative offormula (XI) ##STR31## wherein X' is as defined above.
 5. The process ofclaim 4, further comprising:(g) removing the 4-amino protecting groupfrom the protected derivative of formula (XI) thereby obtaining adaunomycinone derivative of formula (II) ##STR32##
 6. The process ofclaim 4, wherein step (e) is effected by treatment of trifluoroaceticanhydride.
 7. The process of claim 4, wherein step (f) is effected byprotecting the 13-keto group of a 4-demethoxy-4-(protectedamino)-7-deoxy-daunomycinone of formula (XII) ##STR33## by treatmentwith ethylene glycol, brominating the resulting compound at the7-position, and hydrolyzing the 7-bromo and 13-ketal groups to give4-demethoxy-4-N-trifluoroacidamido-daunomycinone of formula (XIII)##STR34##
 8. 4-Demethoxy-4-amino-7-deoxy-daunomycinone.
 9. A process forpreparing 4-demethoxy-7-deoxy-daunomycinone or 4-deoxy-daunomycinone offormula (XIV) ##STR35## wherein R₄ is hydrogen or hydroxy, comprisingthe steps of: diazotizing the 4-amino group of4-demethoxy-4-amino-7-deoxy-daunomycinone or4-demethoxy-4-amino-daunomycinone of formula (XV) ##STR36## wherein R₄is as defined above, and reducing the resulting diazonium compound. 10.The process of claim 9, wherein said reducing step is effected usinghypophosphorus acid.
 11. A process for the preparation of4-demethoxy-4-daunomycinone of formula (XIV) where R₄ is hydroxy, whichcomprises: ##STR37## brominating the 7-position of4-demethoxy-7-deoxy-daunomycinone of formula (XIV) wherein R₄ ishydrogen, followed by treatment with alkali or with silver acetatefollowed by methanolysis.
 12. The process of claim 11, wherein saidbrominating step is conducted using bromine or N-bromosuccinimide.